Receptor-centric solutions for the opioid epidemic: Making the opioid user impervious to overdose death.

This mini-review presents the view that contemporary approaches to stem the tide of opioid overdose deaths are insufficient to make a significant impact. Instead, a focus on the opioid receptor as the ultimate molecular target to directly abolish opioid overdose death is explored. After identifying the key brainstem neurons that control respiration which are inhibited by opioid drugs, genetic techniques targeting the mu opioid receptor are detailed which prevent opioid overdose. This receptor-centric solution for the opioid overdose epidemic can be realized with existing technology and, with sufficient effort, could enter clinical trials within 5 to 10 years.

Predictors of Early Hospice or Death in Patients With Inoperable Lung Cancer Treated With Curative Intent.

INTRODUCTION: Treatment for inoperable stage II to III non-small cell lung cancer (NSCLC) involves chemo-radiotherapy (CRT). However, some patients transition to hospice or die early during their treatment course. We present a model to prognosticate early poor outcomes in NSCLC patients treated with curative-intent CRT. METHODS AND MATERIALS: Across a statewide consortium, data was prospectively collected on stage II to III NSCLC patients who received CRT between 2012 and 2019. Early poor outcomes included hospice enrollment or death within 3 months of completing CRT. Logistic regression models were used to assess predictors in prognostic models. LASSO regression with multiple imputation were used to build a final multivariate model, accounting for missing covariates. RESULTS: Of the 2267 included patients, 128 experienced early poor outcomes. Mean age was 71 years and 59% received concurrent chemotherapy. The best predictive model, created parsimoniously from statistically significant univariate predictors, included age, ECOG, planning target volume (PTV), mean heart dose, pretreatment lack of energy, and cough. The estimated area under the ROC curve for this multivariable model was 0.71, with a negative predictive value of 95%, specificity of 97%, positive predictive value of 23%, and sensitivity of 16% at a predicted risk threshold of 20%. CONCLUSIONS: This multivariate model identified a combination of clinical variables and patient reported factors that may identify individuals with inoperable NSCLC undergoing curative intent chemo-radiotherapy who are at higher risk for early poor outcomes.

Trimodality therapy for patients with stage III non-small-cell lung cancer: A comprehensive surveillance, epidemiology, and end results analysis.

PURPOSE: Debate exists regarding the optimal management for patients with stage III non-small-cell lung cancer (NSCLC). Recent inclusion of chemotherapeutic data in the Surveillance, Epidemiology, and End Results (SEER) database has made it possible to identify patients with NSCLC who received chemotherapy. We hypothesized that patients with stage III NSCLC experience improved overall survival from trimodality therapy (TMT) versus definitive chemoradiation therapy (CRT) alone. MATERIALS AND METHODS: We analyzed the overall survival of stage III NSCLC patients based on the receipt of TMT versus CRT alone. This included crude and adjusted univariate models as well as crude and doubly robust adjusted multivariable analyses, both utilizing propensity score matching and inverse probability of treatment weighting. Factors included in the multivariable analyses included: age, sex, marital status, income, date of diagnosis, primary site, histology, grade, T stage, N stage, and intended treatment. Planned subset analyses were performed for stage III(N2) patients. RESULTS: Adult patients with stage III NSCLC (N = 9008) from the SEER database were included in our analyses. In our univariate analyses, an overall survival benefit was observed for TMT versus CRT (CrudeHR = 0.58, 95% CI = 0.55-0.61, p < 0.001; AdjHR = 0.58, 95% CI = 0.54-0.61, p < 0.001). This persisted in both crude and doubly robust multivariable analyses (CrudeHR = 0.57, 95% CI = 0.53-0.61, p < 0.001; AdjHR = 0.56, 95% CI = 0.53-0.59, p < 0.001). Patients with stage III(N2) disease also demonstrated a significant benefit to OS with TMT versus CRT alone. CONCLUSION: The significant difference in overall survival seen with TMT suggests this may be an effective treatment approach for select patients.

The Role of Postoperative Radiation Therapy for pN2 Non-small-cell Lung Cancer.

BACKGROUND: The role for postoperative radiation therapy (PORT) for patients with non-small-cell lung cancer (NSCLC) with mediastinal lymph node (LN) involvement (pN2 disease) is controversial. We compared surgery alone with PORT among patients with pN2 NSCLC. We then performed subset analyses to better delineate patients that might benefit from PORT. PATIENTS AND METHODS: We conducted a propensity score (PS)-matched, inverse probability of treatment weighting (IPTW) Surveillance, Epidemiology, and End Results (SEER) analysis of patients with pN2 disease from 1989 to 2016 with surgery alone or PORT. Multiple imputation with chained equations was used for missing LN data. RESULTS: A total of 8631 patients were included in this analysis; 4579 underwent surgery alone, and 4052 underwent PORT. Following PS matching and IPTW, there was no difference in overall survival (OS) (hazard ratio [HR], 0.99; P = .76). However, PORT improved OS among a subset of patients with a LN positive to sampled ratio ≥ 50% (HR, 0.90; P = .01). Moreover, there was a trend towards improved OS among this subset, even with chemotherapy (HR, 0.91; P = .09). CONCLUSION: PORT is not associated with an improvement or detriment in OS for all patients with pN2 NSCLC. However, patients with a positive to sampled LN ratio ≥ 50% may benefit, regardless of chemotherapy status. Nevertheless, PORT will remain the standard of care as we await the results of the ongoing LUNG ART trial.

Does Barrett's esophagus respond to chemoradiation therapy for adenocarcinoma of the esophagus?

BACKGROUND: Adenocarcinoma of the esophagus is frequently associated with Barrett's esophagus (BE). The response of esophageal adenocarcinoma to chemoradiation therapy is well described; however, the effect of chemoradiation on tumor-associated BE has not been specifically reported. OBJECTIVE: To determine the response of tumor-associated BE to chemoradiation therapy. DESIGN: Retrospective cohort study. SETTING: A single National Cancer Institute Comprehensive Cancer Care Center experience. PATIENTS: The study cohort consisted of 43 patients with stage I to IVA esophageal adenocarcinoma associated with BE who received either neoadjuvant or definitive chemoradiation therapy and underwent either esophagectomy or surveillance at our institution. MAIN OUTCOME MEASUREMENT: The presence and extent of BE after chemoradiation therapy of esophageal adenocarcinoma associated with endoscopically documented pretreatment BE. RESULTS: BE persisted after chemoradiation therapy in 93% (40/43) of cases (95% CI, 83%-99%). Twenty-seven patients received neoadjuvant chemoradiation therapy before esophagectomy. Persistent BE was detected in all 27 surgical specimens (100%). In 59% (16/27) of the cases, there was complete pathologic tumor response. Sixteen patients received definitive chemoradiation therapy. Persistent pretreatment BE was identified in 88% (14/16) by surveillance endoscopy (95% CI, 60%-98%). The mean length of BE before and after chemoradiation was 6.6 cm and 5.8 cm, respectively (P = .38). LIMITATIONS: Retrospective design, small sample size, and single-site data collection. CONCLUSIONS: Chemoradiation therapy of esophageal adenocarcinoma does not eliminate tumor-associated BE, nor does it affect the length of the BE segment.

Addition of radiotherapy to surgery and chemotherapy improves survival in localized malignant pleural mesothelioma: A Surveillance, Epidemiology, and End Results (SEER) study.

INTRODUCTION: Malignant pleural mesothelioma (MPM) is a devastating disease with poor survival outcomes for most patients. Optimizing therapeutic approaches is thus vital, but has been hampered by a dearth of randomized trials to guide decision making. We used a population-level database to evaluate the impact of radiotherapy as a component of trimodality therapy on overall survival (OS) in MPM. METHODS: We retrospectively reviewed the SEER Radiation/Chemotherapy database for patients with MPM who received surgery and chemotherapy, with or without radiotherapy. A propensity score-matched analysis with inverse probability of treatment weighting (IPTW) was performed. Weight-adjusted univariate KM analysis was performed and doubly robust, IPTW-adjusted multivariable cox proportional hazards regression modeling was also performed to quantify the effect of radiotherapy on OS in trimodality therapy for MPM. RESULTS: 1015 patients were identified. 678 patients received surgery and chemotherapy, and 337 patients received trimodality therapy. For patients with localized disease, OS was significantly improved with trimodality therapy (HR 0.56, CI 0.4 - 0.8, p = 0.001), which persisted with IPTW adjustment (HR 0.65, CI 0.49 - 0.95, p = 0.0248). No significant benefit was seen for patients with regional or distant disease. On multivariate analysis, positive predictors of survival after IPTW adjustment were female sex, diagnosis after 2005, and left-sided disease. CONCLUSIONS: These findings support a significant benefit to OS by incorporating radiotherapy as a component of trimodality therapy for patients with localized MPM compared to only surgery and chemotherapy. It does not provide a significant overall survival benefit for patients with regional or metastatic disease.

Nociceptin produces antinociception after spinal administration in amphibians.

Nociceptin, also known as orphanin FQ, is a opioid-like neuropeptide that mediates its effects at the nociceptin receptor, a member of the G protein-coupled receptor superfamily. In mammals, nociceptin produces analgesia after spinal administration, however the role of nociceptin and nociceptin receptors in the modulation of noxious stimuli in non-mammalian species has not been examined. In an amphibian pain model using the acetic acid test with Rana pipiens, nociceptin and nociceptin1-13 amide produced dose-dependent antinociception (1-100 nmol), blocked by the nociceptin antagonist, [Nphe1]-nociceptin1-13 amide (30 nmol), but not the opioid antagonist, naltrexone (100 nmol/g, s.c.). Conversely, the antinociceptive effects of micro, delta, and kappa opioid receptor agonists were not blocked by the nociceptin antagonist. Nociceptin and nociceptin1-13 amide were the least potent of the opioid agonists tested. These studies demonstrate that spinal nociceptin receptors and not opioid receptors mediate the antinociceptive effect of nociceptin. Considered with previous findings, these behavioral data supports a role for nociceptin inhibition of spinal nociception in amphibians and perhaps all vertebrates.

Amelioration of Mucositis in Proton Therapy of Fanconi Anemia Fanca-/- Mice by JP4-039.

BACKGROUND/AIM: We tested JP4-039, a GS-nitroxide radiation damage mitigator in proton therapy of Fanconi anemia (FA) mice. MATERIALS AND METHODS: Fanca-/- and Fanca+/+ bone marrow stromal cells were pre-treated with JP4-039 and irradiated with either protons or photons (0-10 GyRBE) followed by clonogenic survival and ß-Galactosidase senescence analysis. Fanca-/- and Fanca+/+ mice were pretreated with JP4-039 for 10 min prior to oropharyngeal irradiation with either protons or photons (0 or 30 GyRBE) followed by sacrifice and measurement of oral cavity ulceration, distant hematopoietic suppression, and real-time polymerase chain reaction analysis. RESULTS: JP4-039 reduced oral cavity ulceration in Fanca-/- mice, transcripts Nfkb, Ap1, Sp1, and Nrf2, and proton therapy induced distant marrow suppression. CONCLUSION: JP4-039 protected Fanca-/- and Fanca+/+ cells and mouse oral cavity from both proton and photon radiation.

A pharmacological comparison of the cloned frog and human mu opioid receptors reveals differences in opioid affinity and function.

This study presents a direct comparison of the ligand binding and signaling profiles of a mammalian and non-mammalian mu opioid receptor. Opioid ligand binding and agonist potencies were determined for an amphibian (Rana pipiens) mu opioid receptor (rpMOR) and the human mu opioid receptor (hMOR) in transfected, intact Chinese hamster ovary (CHO) cells. Identical conditions were employed such that statistically meaningful differences between the two receptors could be determined. Identifying these differences is an important first step in understanding how evolutionary changes affect ligand binding and signaling in vertebrate opioid receptors. As expected, the rank of opioid ligand affinity for rpMOR and hMOR was consistent with the ligands' previously characterized type-selectivity. However, most of the opioid ligands tested had significant differences in affinity for rpMOR and hMOR. For example, the mu-selective agonist, DAMGO ([d-Ala(2), N-Me-Phe(4), Gly(5)-ol]-enkephalin), had a 10.9-fold greater affinity (K(i)) for hMOR (K(i)=268 nM) than rpMOR (K(i)=2914 nM). In addition, differences in signaling between these receptors were found by measuring inhibition of cAMP accumulation by morphine or DAMGO. DAMGO was significantly more potent (13.6-fold) in CHO cells expressing hMOR versus those expressing rpMOR. In addition, a significantly greater maximal inhibition was elicited by both opioid agonists in cells expressing hMOR. In summary, this study supports an ongoing effort to better understand how vertebrate evolution has shaped opioid receptor properties and function.

Compensator-based intensity-modulated radiation therapy for malignant pleural mesothelioma post extrapleural pneumonectomy.

The present work investigated the potential of compensator-based intensity-modulated radiation therapy (CB-IMRT) as an alternative to multileaf collimator (MLC)-based intensity-modulated radiation therapy (IMRT) to treat malignant pleural mesothelioma (MPM) post extrapleural pneumonectomy. Treatment plans for 4 right-sided and 1 left-sided MPM post-surgery cases were generated using a commercial treatment planning system, XIO/CMS (Computerized Medical Systems, St. Louis, MO). We used a 7-gantry-angle arrangement with 6 MV beams to generate these plans. The maximum required field size was 30 x 40 cm. We evaluated IMRT plans with brass compensators (.Decimal, Sanford, FL) by examining isodose distributions, dose-volume histograms, metrics to quantify conformal plan quality, and homogeneity. Quality assurance was performed for one of the compensator plans. Conformal dose distributions were achieved with CB-IMRT for all 5 cases, the average planning target volume (PTV) coverage being 95.1% of the PTV volume receiving the full prescription dose. The average lung V20 (volume of lung receiving 20 Gy) was 1.8%, the mean lung dose was 6.7 Gy, and the average contralateral kidney V15 was 0.6%. The average liver dose V30 was 34.0% for the right-sided cases and 10% for the left-sided case. The average monitor units (MUs) per fraction were 980 MUs for the 45-Gy prescriptions (mean: 50 Gy) and 1083 MUs for the 50-Gy prescriptions (mean: 54 Gy). Post surgery, CB-IMRT for MPM is a feasible IMRT technique for treatment with a single isocenter. Compensator plans achieved dose objectives and were safely delivered on a Siemens Oncor machine (Siemens Medical Solutions, Malvern, PA). These plans showed acceptably conformal dose distributions as confirmed by multiple measurement techniques. Not all linear accelerators can deliver large-field MLC-based IMRT, but most can deliver a maximum conformal field of 40 x 40 cm. It is possible and reasonable to deliver IMRT with compensators for fields this size with most conventional linear accelerators.

Improved Survival With Increased Time-To-Radiation and Sequential Chemotherapy After Surgery for pN2 Non-Small-cell Lung Cancer.

BACKGROUND: Currently, the ideal timing for postoperative radiotherapy (PORT) and chemotherapy is unknown. The present study evaluated their relative timing on overall survival (OS) using the National Cancer Database (NCDB). MATERIALS AND METHODS: The NCDB was queried for patients from 2004 to 2012 with resected non-small-cell lung cancer (NSCLC), pathologically involved N2 (pN2) nodes, and negative margins. All patients underwent adjuvant chemotherapy and external beam radiotherapy. The time to radiation (TTR) was determined from the date of surgery to the start of PORT, with the exclusion of those receiving PORT < 4 weeks or > 24 weeks postoperatively. Early and late TTR was dichotomized at 8 weeks after receiver operating characteristic analysis. Multivariate Cox regression analysis was conducted to predict the variables significantly associated with survival. RESULTS: A total of 1629 patients were eligible for analysis. Of the 1629 patients, 703 had received PORT < 8 weeks and 926 had received PORT ≥ 8 weeks postoperatively. The receipt of PORT after 8 weeks was associated with better OS (P = .0044). No significant differences were found in survival in the concurrent group comparing early and later TTR (P = .9119). However, a significant OS benefit was found for sequential chemotherapy with an increased TTR (P = .0045). Older age, male sex, shorter distance traveled, increased nodal positivity, larger tumor size, higher Charlson/Deyo comorbidity score, and early TTR were associated with inferior survival on multivariate analysis. CONCLUSION: A TTR of ≥ 8 weeks with sequential chemotherapy in the setting of PORT was associated with improved survival in patients with NSCLC with pN2 nodes.

Induction chemoradiotherapy versus chemotherapy alone for superior sulcus lung cancer.

OBJECTIVES: Although treatment of superior sulcus tumors with induction chemoradiotherapy (CRT) followed by surgery employed in the Intergroup INT-0160 trial is widely adopted as a standard of care, there may be significant associated morbidity and mortality. We describe our experience using standard and alternative induction regimens to assess survival rates and treatment toxicity in these patients. MATERIALS AND METHODS: Electronic medical records of all patients who underwent multimodality treatment including resection of lung cancer invading the superior pulmonary sulcus between 1994 and 2016 were retrospectively reviewed. Multivariable Cox Proportional Hazards model was constructed. RESULTS: Of 102 consecutive patients, 53 (52%) underwent induction CRT, 34 (33%) underwent induction chemotherapy only (Ch) followed by adjuvant radiotherapy, and 15 (15%) underwent no induction therapy followed by adjuvant therapy. There were 2 postoperative deaths (1.9%). To date, 42 patients are alive with a median follow-up 72.5 months. Overall 5-year survival rate was 45.4%. Survival was significantly influenced by age, FEV1, positive resection margins, surgical complications, but not the induction regimen. CRT resulted in higher complete pathological response rate than Ch: 38% vs. 3% (p < 0.001). CRT was associated with higher post-operative re-intubation rate: 13% vs. 0% (p = 0.03). CONCLUSIONS: Our single-institutional experience indicated that while induction CRT produced greater complete pathological response than Ch, it also increased the risk of post-operative complications. With careful patient selection, induction Ch followed by adjuvant radiotherapy may provide comparable survival outcomes to induction CRT. Since induction Ch is associated with lower risk of complications, it may be a particularly desirable choice for patients with impaired performance status.

Quantitatively Excessive Normal Tissue Toxicity and Poor Target Coverage in Postoperative Lung Cancer Radiotherapy Meta-analysis.

BACKGROUND: A previous meta-analysis (MA) found postoperative radiotherapy (PORT) in lung cancer patients to be detrimental in N0/N1 patients and equivocal in the N2 setting. We hypothesized that treatment plans generated using MA protocols had worse dosimetric outcomes compared to modern plans. PATIENTS AND METHODS: We retrieved plans for 13 patients who received PORT with modern planning. A plan was recreated for each patient using the 8 protocols included in MA. Dosimetric values were then compared between the modern and simulated MA plans. RESULTS: A total of 104 MA plans were generated. Median prescribed dose was 50.4 (range, 50-60) Gy in the modern plans and 53.2 (30-60) Gy in the MA protocols. Median planning volume coverage was 96% (93%-100%) in the modern plans, versus 58% (0%-100%) in the MA plans (P < .001). Internal target volume coverage was 100% (99%-100%) versus 65% (0%-100%), respectively (P < .001). Organs at risk received the following doses: spinal cord maximum dose, 36.8 (4.6-50.4) Gy versus 46.8 (2.9-74.0) Gy (P < .001); esophageal mean dose, 22.9 (5.5-35) Gy versus 30.5 (11.1-52.5) Gy (P = .003); heart V30 (percentage of volume of an organ receiving at least a dose of 30 Gy), 16% (0%-45%) versus 35% (0%-79%) (P = .047); mean lung dose, 12.4 (3.4-24.3) Gy versus 14.8 (4.1-27.4) Gy (P = .008); and lung V20, 18% (4%-34%) versus 25% (8%-67%) (P = .023). CONCLUSION: We quantitatively confirm the inferiority of the techniques used in the PORT MA. Our analysis showed a lower therapeutic ratio in the MA plans, which may explain the poor outcomes in the MA. The findings of the MA are not relevant in the era of modern treatment planning.

Assessment of lung tumor motion and setup uncertainties using implanted fiducials.

PURPOSE: The purpose of this work was to assess the magnitude of setup uncertainties and respiratory-induced motion of lung tumors by monitoring the location of fiducials implanted in the vicinity of the tumors. METHODS AND MATERIALS: Gold fiducials were implanted in the periphery of lung tumors in 5 patients who had Stage III non-small-cell lung cancer. Fiducial motion was measured using weekly repeated four-dimensional computed tomography (4DCT) imaging and during gated treatment each day using an electronic portal imaging device (EPID). Setup uncertainties were quantified using both the EPID images and the 4DCT data sets. RESULTS: We observed a reduction in fiducial motion (left/right and superior/inferior directions) during gated treatment; however, large gated motion was present (>1 cm). Systematic and random uncertainties based on patient setup ranged from 4 to 6 mm in all three directions as measured using fiducials on gated EPID images and repeat 4DCTs, and using bony anatomy on repeat 4DCTs. CONCLUSIONS: Respiratory gating may be an effective method of reducing average motion during the course of treatment, but large motion is still possible when delivering gated treatment. Setup uncertainties were on the order of, if not larger than, residual gated motion. We recommend careful consideration of all sources of error before reducing margins on the basis of respiratory motion management alone without a strategy for accurate patient setup on a daily basis.

Dose-dependent pulmonary toxicity after postoperative intensity-modulated radiotherapy for malignant pleural mesothelioma.

PURPOSE: To determine the incidence of fatal pulmonary events after extrapleural pneumonectomy and hemithoracic intensity-modulated radiotherapy (IMRT) for malignant pleural mesothelioma. METHODS AND MATERIALS: We retrospectively reviewed the records of 63 consecutive patients with malignant pleural mesothelioma who underwent extrapleural pneumonectomy and IMRT at the University of Texas M. D. Anderson Cancer Center. The endpoints studied were pulmonary-related death (PRD) and non-cancer-related death within 6 months of IMRT. RESULTS: Of the 63 patients, 23 (37%) had died within 6 months of IMRT (10 of recurrent cancer, 6 of pulmonary causes [pneumonia in 4 and pneumonitis in 2], and 7 of other noncancer causes [pulmonary embolus in 2, sepsis after bronchopleural fistula in 1, and cause unknown but without pulmonary symptoms or recurrent disease in 4]). On univariate analysis, the factors that predicted for PRD were a lower preoperative ejection fraction (p = 0.021), absolute volume of lung spared at 10 Gy (p = 0.025), percentage of lung volume receiving >or=20 Gy (V(20); p = 0.002), and mean lung dose (p = 0.013). On multivariate analysis, only V20 was predictive of PRD (p = 0.017; odds ratio, 1.50; 95% confidence interval, 1.08-2.08) or non-cancer-related death (p = 0.033; odds ratio, 1.21; 95% confidence interval, 1.02-1.45). CONCLUSION: The results of our study have shown that fatal pulmonary toxicities were associated with radiation to the contralateral lung. V20 was the only independent determinant for risk of PRD or non-cancer-related death. The mean V20 of the non-PRD patients was considerably lower than that accepted during standard thoracic radiotherapy, implying that the V20 should be kept as low as possible after extrapleural pneumonectomy.

The opioid antagonist, beta-funaltrexamine, inhibits chemokine expression in human astroglial cells.

Emerging evidence indicates that neuroinflammatory responses in astroglia, including chemokine expression, are altered by opioids. Astroglial chemokines, such as CXCL10, are instrumental in response to many neuropathological insults. Opioid mediated disruption of astroglial CXCL10 expression may be detrimental in opioid abusers or patients receiving acute opioid therapy. We have characterized the in vitro effects of opioids on CXCL10 protein expression in human astroglial (A172) cells. The proinflammatory cytokine, tumor necrosis factor (TNF)alpha induced CXCL10 expression in A172 cells. Using MG-132, helenalin and SN50 [inhibitors of the transcription factor, nuclear factor (NF)-kappaB], we determined that NF-kappaB activation is instrumental in TNFalpha-induced CXCL10 expression in A172 astroglia. Morphine exposure during the 24 h TNFalpha stimulation period did not alter CXCL10 expression. However, fentanyl, a more potent mu-opioid receptor (MOR) agonist, inhibited TNFalpha-induced CXCL10 expression. Interestingly, neither the non-selective opioid receptor antagonist, naltrexone nor beta-funaltrexamine (beta-FNA), a highly selective MOR antagonist, blocked fentanyl mediated inhibition of TNFalpha-induced CXCL10 expression. Rather, beta-FNA dose-dependently inhibited TNFalpha-induced CXCL10 expression with a greater potency than that observed for fentanyl. Immunoblot analysis indicated that morphine, fentanyl and beta-FNA each reduced TNFalpha-induced nuclear translocation of NF-kappaB p65. These data show that beta-FNA and fentanyl inhibit TNFalpha-induced CXCL10 expression via a MOR-independent mechanism. Data also suggest that inhibition of TNFalpha-induced CXCL10 expression by fentanyl and beta-FNA is not directly related to a reduction in NF-kappaB p65 nuclear translocation. Further investigation is necessary in order to fully elucidate the mechanism through which these two opioid compounds inhibit CXCL10 expression. Understanding the mechanism by which chemokine expression is suppressed, particularly by the opioid antagonist, beta-FNA, may provide insights into the development of safe and effective treatments for neuroinflammation.

Treatment of non-small cell lung cancer-stage IIIA: ACCP evidence-based clinical practice guidelines (2nd edition).

STUDY OBJECTIVES: Stage IIIA non-small cell lung cancer represents a relatively heterogeneous group of patients with metastatic disease to the ipsilateral mediastinal (N2) lymph nodes and also includes T3N1 patients. Presentations of disease range from apparently resectable tumors with occult microscopic nodal metastases to unresectable, bulky multistation nodal disease. This review explores the published clinical trials to make treatment recommendations in this controversial subset of lung cancer. DESIGN, SETTING, AND PARTICIPANTS: Systematic searches were made of MEDLINE, HealthStar, and Cochrane Library databases up to May 2006, focusing primarily on randomized trials, with inclusion of selected metaanalyses, practice guidelines, and reviews. Study designs and results are summarized in evidence tables. MEASUREMENT AND RESULTS: The evidence derived from the literature now appears to support routine adjuvant chemotherapy after complete resection of stage IIIA lung cancer encountered unexpectedly at surgery. However, using neoadjuvant therapy followed by surgery for known stage IIIA lung cancer as a routine therapeutic option is not supported by current published randomized trials. Combination chemoradiotherapy, especially delivered concurrently, is still the preferred treatment for prospectively recognized stage IIIA lung cancer with all degrees of mediastinal lymph node involvement. Current and future trials may modify these recommendations. CONCLUSIONS: Multimodality therapy of some type appears to be preferable in all subsets of stage IIIA patients. However, because of the relative lack of consistent randomized trial data in this subset, the following evidence-based treatment guidelines lack compelling evidence in most scenarios.

Cloning and bioinformatics of amphibian mu, delta, kappa, and nociceptin opioid receptors expressed in brain tissue: evidence for opioid receptor divergence in mammals.

Opioid agonists produce analgesia in humans and other mammals by binding to three distinct types of G protein-coupled receptors; mu (MOR), delta (DOR), and kappa (KOR) opioid receptors. A fourth member of the opioid receptor family is the nociceptin or orphanin FQ receptor (ORL), however the role of the ORL receptor in analgesia is less clear. In the Northern grass frog, Rana pipiens, systemic and central administration of morphine and selective MOR, DOR, and KOR agonists produced dose-dependent antinociceptive effects blocked by the general opioid antagonist, naltrexone. The present study reports on the sequence, expression, and bioinformatics of four opioid receptor cDNAs cloned from Rana pipiens; rpMOR, rpDOR, rpKOR, and rpORL. These were the first opioid receptors cloned from a species of Class Amphibia, are selectively expressed in brain tissue, and show 70-84% identity to their homologous mammalian opioid receptors. Comparisons within species showed that MOR, DOR, and KOR proteins are significantly less divergent in earlier-evolved vertebrates compared to humans and other mammals. Among the four types of opioid receptors, MOR proteins show the least sequence variation among the six vertebrate species. Additionally, phylogenetic analysis supports the hypothesis that the family of opioid receptor proteins are coded by four genes that arose from two gene duplications of a single ancestral opioid receptor gene.

Xendorphin B1, a novel opioid-like peptide determined from a Xenopus laevis brain cDNA library, produces opioid antinociception after spinal administration in amphibians.

Prodynorphins (PDYNs) from the African clawed frog (Xenopus laevis), originally described as 'proxendorphins', are novel members of the family of opioid-like precursor polypeptides and were recently discovered based on polymerase chain reaction (PCR) isolates from a Xenopus brain cDNA library. This amphibian prodynorphin was found in two isoforms, (Xen)PDYN-A and (Xen)PDYN-B, consisting of 247 and 279 amino acids, respectively. Each prepropeptide contains five potential opioid-like peptides, collectively named xendorphins. One of these, xendorphin B1 ((Xen)PDYN-B sequence 96-111: YGGFIRKPDKYKFLNA), is a hexadecapeptide that displaced [3H]naloxone and the radiolabelled kappa opioid, [3H]dynorphin A (1-17), with nanomolar affinity from rat brain membranes. Using the acetic acid pain test, the present study examined the antinociceptive effects of spinally administered xendorphin B1 in amphibians. Xendorphin B1 produced a long-lasting and dose-dependent antinociceptive effect in the Northern grass frog (Rana pipiens) with an ED50 value of 44.5 nmol/frog. The antinociceptive effects of xendorphin B1 were significantly blocked by pretreatment with the non-selective opioid antagonist, naltrexone. This is the first report of the in vivo characterization of a non-mammalian prodynorphin-derived peptide and suggests that xendorphin peptides may play a role in the modulation of noxious information in vertebrates.

The opioid antagonist, ß-funaltrexamine, inhibits lipopolysaccharide-induced neuroinflammation and reduces sickness behavior in mice.

Brain pathologies such as neurodegenerative diseases, infection, traumatic brain injury, and mood disorders produce enormous personal and economic burdens. It is well established that neuroinflammation plays an important role in the etiology and/or manifestation of such disorders. Previously, we discovered that beta-funaltrexamine (ß-FNA) inhibits inflammatory signaling in human astrocytes in vitro, resulting in reduced expression of proinflammatory cytokines/chemokines. The present study examines the effects of peripherally administered ß-FNA on lipopolysaccharide (LPS)-induced neuroinflammation and sickness behavior in vivo. Adult male C57BL/6J mice were administered ß-FNA and were then immediately administered bacterial lipopolysaccharide (LPS). At 24h post-injections, sickness behavior was assessed in an open-field test. Following behavioral analysis plasma and brains were collected. Levels of interleukin-6 (IL-6), interferon-γ inducible protein-10 (CXCL10), and monocyte chemoattractant protein-1 (CCL2) were determined by enzyme-linked immunosorbant assay (ELISA). At 24h post-LPS injection, IL-6, CCL2 and CXCL10 were increased in the plasma, whereas, only CCL2 and CXCL10 were elevated in the brain. ß-FNA significantly inhibited LPS-induced CXCL10 and CCL2 expression in brain, but minimally or not at all in the plasma. LPS-induced sickness behavior, as indicated by a reduction in distance moved, was prevented by ß-FNA. Overall, CXCL10 expression in the brain was most positively and significantly correlated with sickness behavior; whereas, anxiety-like behavior was most positively and significantly correlated with IL-6 and CCL2 levels in the plasma and levels of CXCL10 and CCL2 in the brain. The reduction in sickness behavior may be in part due to decreased chemokine expression in the brain; further examination of the anti-inflammatory and neuroprotective effects of ß-FNA is warranted.